Genetic predictors of long‐term toxicities after radiation therapy for breast cancer

Abstract

Telangiectasia and subcutaneous fibrosis are the most common late dermatologic side effects observed in response to radiation treatment. Radiotherapy acts on cancer cells largely due to the generation of reactive oxygen species (ROS). ROS also induce normal tissue toxicities. Therefore, we investigated if genetic variation in oxidative stress-related enzymes confers increased susceptibility to late skin complications. Women who received radiotherapy following lumpectomy for breast cancer were followed prospectively for late tissue side effects after initial treatment. Final analysis included 390 patients. Polymorphisms in genes involved in oxidative stress-related mechanisms (GSTA1, GSTM1, GSTT1, GSTP1, MPO, MnSOD, eNOS, CAT) were determined from blood samples by MALDI-TOF. The associations between telangiectasia and genotypes were evaluated by multivariate unconditional logistic regression models. Patients with variant GSTA1 genotypes were at significantly increased risk of telangiectasia (OR 1.86, 95% CI 1.11-3.11). Reduced odds ratios of telangiectasia were noted for women with lower-activity eNOS genotype (OR 0.58, 95% CI 0.36-0.93). Genotype effects were modified by follow-up time, with the highest risk observed after 4 years of radiotherapy for gene polymorphisms in ROS-neutralizing enzymes. Decreased risk with eNOS polymorphisms was significant only among women with less than 4 years of follow-up. All other risk estimates were nonsignificant. Late effects of radiation therapy on skin appear to be modified by variants in genes related to protection from oxidative stress. The application of genomics to outcomes following radiation therapy holds the promise of radiation dose adjustment to improve both cosmetic outcomes and quality of life for breast cancer patients. ' 2007 Wiley-Liss, Inc.Key words: genetic polymorphisms; reactive oxygen species; longterm toxicities; radiation therapy; breast cancer Lumpectomy followed by radiation therapy is an effective treatment for women with early-stage breast cancer and is offered for the purpose of breast conservation and better cosmetic results. 1With recent advances in radiation techniques and computer tomography (CT) dose planning, it is possible to reduce cardiac toxicity due to radiotherapy; however, skin reactions, pain, breast edema and poor cosmetic results remain as health concerns of treated breast cancer patients over time. 2,3 Because of the differences in physiological response of various skin layers to radiation, telangiectasia and subcutaneous fibrosis are among the most common long-term skin side effects of radiation therapy, with higher grade correlated with poor cosmesis. 4 The process of endothelium reconstruction is radiation dosedependent, progresses over months and years and leads to the increase in severity of both telangiectasia and fibrosis.5-7 Besides duration, radiation dose and schedule, 8,9 and other factors such as radiation fields, type of surgery, increased breast size, tamoxifen treatment, chemotherapy, acute skin reactions, age, race...

Genetic polymorphisms in DNA repair and damage response genes and late normal tissue complications of radiotherapy for breast cancer

“…Data on late effects of radiotherapy as well as information on demographic and epidemiological factors were available for 421 breast cancer patients, as reported earlier (Lilla et al, 2007;Kuptsova et al, 2008). After a median follow-up time of 51 months (range 36 -77 months), the most common symptoms of scores X2, which were observed included telangiectasia (32.1%), impairment of the general condition (15.9%), fibrosis (7.1%), lymphatic edema in the arm and breast (6.2%), and pain (5.5%).…”

Genetics and genomics of radiotherapy toxicity: towards prediction

“…Cells able to undergo apoptosis or having impaired cell cycle arrest following irradiation tend to be radiosensitive [49-51]. As ROS/RNOS are important (Figure 2), genes encoding antioxidants involved in free-radical scavenging are also implicated, for example, superoxide dismutase ( SOD1 ), glutathione S -transferases (for example, GSTA5 ) and catalase ( CAT ), and germline genetic variations that predispose to increased levels of ROS may predispose to increased radiation toxicity [52]. ROS/RNOS pathways are less widely studied than those involving DNA repair in terms of cellular and clinical radiosensitivity, but there is evidence that changing levels of antioxidants can alter cellular radiosensitivity [53,54].…”

Increased Susceptibility of Breast Cancer Cells to Stress Mediated Inhibition of Protein Synthesis

“…It is recently becoming evident that capdependent protein synthesis pathway is an integrator and amplifier of many essential oncogenic signals (8). Radiation therapy has been found to act on cancer cells largely due to generation of reactive oxygen species, which also induce normal tissue toxicity (9). One of the areas that remain unexplored is the sensitivity of initiation of protein synthesis in untransformed and cancer cells to various oxidative stresses.…”